Tricyclic Analogues of Epidithiodioxopiperazine Alkaloids with Promising In Vitro and In Vivo Antitumor Activity.
Tricyclic Analogues of Epidithiodioxopiperazine Alkaloids with Promising In Vitro and In Vivo Antitumor Activity.
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DOI：
10.1039/c5sc01536g
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发表时间：
2015
期刊：
影响因子：
8.4
通讯作者：
Overman LE
中科院分区：
文献类型：
--
作者：
Baumann M;Dieskau AP;Loertscher BM;Walton MC;Nam S;Xie J;Horne D;Overman LE
1，4-二氧代六氢-6H-3，8a-epidithiopyrrolo [1，2-a]吡嗪的短合成将使这些结构新颖且有前途的临床抗肿瘤候选物的未来机制和翻译研究成为可能。表聚硫代二氧代哌嗪（epipolithiodioxipiperazine，ETP）生物碱是一类结构复杂的生物碱，具有很强的抗肿瘤活性.然而，它们的高毒性和与各种生物受体的相互作用损害了它们的治疗潜力。为了减轻这些缺点，开发了表二硫二氧代哌嗪生物碱的三环类似物的短立体控制结构。针对两种侵袭性癌细胞系对此类结构的小文库进行的评估定义了初始结构-活性关系（SAR），其鉴定了1，4-二氧六氢-6H-3，8a-epidithiopyrrolo [1，2-a]吡嗪3c和相关结构作为特别有前途的抗肿瘤剂。ETP生物碱类似物3c在体外对实体瘤和血液肿瘤都表现出低纳摩尔活性。此外，在腹膜内（IP）或口服施用后，3c显著抑制黑素瘤和肺癌的小鼠异种移植物模型中的肿瘤生长，而没有明显的毒性迹象。在这个系列中的分子的短合成将使未来的机制和这些结构新颖的和非常有前途的临床抗肿瘤候选人的翻译研究。
A short synthesis of 1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazines will enable future mechanistic and translational studies of these structurally novel and promising clinical antitumor candidates. Epipolythiodioxopiperazine (ETP) alkaloids are structurally elaborate alkaloids that show potent antitumor activity. However, their high toxicity and demonstrated interactions with various biological receptors compromises their therapeutic potential. In an effort to mitigate these disadvantages, a short stereocontrolled construction of tricyclic analogues of epidithiodioxopiperazine alkaloids was developed. Evaluation of a small library of such structures against two invasive cancer cell lines defined initial structure–activity relationships (SAR), which identified 1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine 3c and related structures as particularly promising antitumor agents. ETP alkaloid analogue 3c exhibits low nanomolar activity against both solid and blood tumors in vitro. In addition, 3c significantly suppresses tumor growth in mouse xenograft models of melanoma and lung cancer, without obvious signs of toxicity, following either intraperitoneal (IP) or oral administration. The short synthesis of molecules in this series will enable future mechanistic and translational studies of these structurally novel and highly promising clinical antitumor candidates.